1. Field of the Invention
The present invention relates to the use of glycyrrhizin and its derivatives for inhibition of MCP-1 production and the production of an MCP-1 production inhibitor, a method for inhibiting MCP-1 production, a method for controlling infections through the inhibition of MCP-1 production, and a pharmaceutical composition for the same.
2. Description of the Related Art
<MCP-1 Chemokines>
Cytokines are proteins produced by lymphocytes and other cells, and act on cells having receptors to them to carry out cell growth, differentiation and expression of function. In addition, cytokines also include a group of proteins referred to as chemokines having the action of causing migration of leukocytes. These chemokines have a common structure in which they have four cysteine residues, and are classified into subfamilies such as CXC, CC and so forth according to the motif formed by two cysteine residues on the N terminal side.
Chemokines belonging to the CXC subfamily have a sequence in which the first two cysteine residues on the N terminal side surround one amino acid, namely have CXC, and induce chemotaxis in vitro particularly in neutrophils. On the other hand, chemokines belonging to the CC subfamily differ from those belonging to the CXC subfamily in that they have an amino acid sequence in which the first two cysteine residues on the N terminal side are arranged in a row directly without having an amino acid between them, and are known to induce chemotaxis in vitro in monocytes, macrophages, T cells, NK cells, eosinophils and so forth.
MCP-1 (monocytechemoattractant (chemotactic) protein-1) is a CC chemokine that is a protein composed of 76 amino acids and having a molecular weight of 8,000 to 18,000. When monocytes, macrophages, fibroblasts or vascular endothelial cells and so forth are stimulated by a bacterial infection and the like, MCP-1 is thought to be produced and secreted by these cells and promote local tissue infiltration by macrophages, T cells and so forth at the site of the infection. In addition, MCP-1 has been observed to be independently and constantly produced by certain types of tumor cells.
Infection resistance to various infectious diseases is known to decrease when the type 2 T cell reaction becomes dominant. In MCP-1 knockout mice, type 2 T cells do not appear. In other words, MCP-1 has been demonstrated to be required for establishment of a type 2 T cell reaction. If it were possible to stop the production of MCP-1, an individual would not have to go through a state in which the type 2 T cell reaction is dominant, thereby preventing that individual from succumbing to an infectious disease. For example, in the case the type 2 T cell reaction has become dominant with MCP-1, infection sensitivity increases 100-fold in the case of Herpes infections and 50-fold in the case of Candida infections, thereby resulting in exacerbation of Herpes encephalitis, Cryptococcus encephalitis and pneumonia. In addition, in a state in which the type 2 T cell reaction has become dominant, since the anti-tumor immunity of an individual to tumors is not induced, there is greater susceptibility to accelerated tumor growth and opportunistic infections in individuals with cancer.
Thus, if it were possible to inhibit the action of MCP-1, it is thought that desirable effects would be obtained in these diseases and so forth.